Bone loss caused by trauma, neoplasia, congenital defects or periodontal disease is a major cause of disability and human suffering. The limitations of current surgical approaches to treating bone loss have stimulated the development of tissue engineering (TE) strategies for bone regeneration involving a variety of osteoinductive biodegradable scaffolds. In one approach, TE scaffolds were developed containing peptides that mimic extracellular matrix molecules such as collagen. These peptides bind integrin receptors on the surface of skeletal progenitor cells. However, progenitors also interact with collagen via discoidin domain receptor 2 (DDR2), an understudied but important collagen receptor that is essential for bone formation. Our preliminary studies shown DDR2 to also be essential for regeneration of calvarial sub-critical-size defects and tibial fractures. This demonstrates a novel role for DDR2 in bone regeneration and suggests that DDR2-based therapeutics could be a new class of bone regeneration agents. To this end, a triple-helical peptide comprising the DDR binding domain of collagen binds/activates DDR2 and stimulates osteoblast differentiation. Based on these exciting data, we propose the following hypothesis: DDR2 is a critical factor for bone regeneration; stimulating its activity either by regulating its levels or activity using scaffold containing DDR2-binding peptides will positively stimulate bone regeneration. DDR2 stimulates regeneration by functioning together with collagen-binding integrins to induce osteoblast differentiation in skeletal progenitor cells. Studies will develop this exciting new area by achieving the following aims: 1. Establish the requirement for DDR2 in bone regeneration. Gain and loss-of-function approaches will be used to evaluate the requirement for DDR2 in craniofacial regeneration. 2. Develop and evaluate scaffolds containing Ddr2 and integrin-activating peptides in bone regeneration. The feasibility of using DDR2-binding peptides alone and together with integrin-binding peptides in nanofibrous hollow microsphere TE scaffolds will be assessed in a craniofacial regeneration model. Expected outcomes include: 1) demonstration of a functional role for DDR2 in skeletal regeneration in vivo, 2) determine if there is cross-talk between DDR2 and integrin-activating peptides during osteoblast differentiation, 3) complete proof-of-principle studies showing the value of DDR2-activating scaffolds for bone TE applications. Studies will support future projects aimed at developing DDR2-based therapeutics.